3-benzylamino-2-phenylpiperidines as neurokinin antagonists

ABSTRACT

The invention relates to piperidine derivatives of formula (I) ##STR1## wherein R 1  is a C 2-4  alkoxy group; R 2  is ##STR2## R 3  is a hydrogen or halogen atom; R 4  and R 5  may each independently represent a hydrogen or halogen atom, or a C 1-4  alkyl, C 1-4  alkoxy or trifluoromethyl group; 
     and pharmaceutically acceptable derivatives thereof, to processes for their preparation, and their use in the treatment of conditions mediated by tachykinins.

This application is a 371 of PCT/EP96/01169 filed Mar. 19, 1996.

The present invention relates to piperidine derivatives, to processesfor their preparation, pharmaceutical compositions containing them andtheir medical use.

In particular the invention relates to novel compounds which are potentand specific antagonists of tachykinins, including substance P and otherneurokinins.

3-Aminopiperidine derivatives described as having substance P antagonistactivity are disclosed in, for example, WO-A-9300331, WO-A-9301170,WO-A-9413663 and WO-A-95/08549.

The present invention provides compounds of formula (I) ##STR3##

wherein R¹ is a C₂₋₄ alkoxy group;

R² is ##STR4##

R³ is a hydrogen or halogen atom;

R⁴ and R⁵ may each independently represent a hydrogen or halogen atom,or a C₁₋₄ alkyl, C₁₋₄ alkoxy or trifluoromethyl group;

and pharmaceutically acceptable derivatives thereof.

By "a pharmaceutically acceptable derivative" is meant anypharmaceutically acceptable salt or solvate of a compound of formula (I)or any other compound which, upon administration to the recipient, iscapable of providing (directly or indirectly) a compound of formula (I)or an active metabolite or residue thereof.

It will be appreciated by those skilled in the art that the compounds offormula (I) may be modified to provide pharmaceutically acceptablederivatives thereof at any of the functional groups in the compounds offormula (I). It will be appreciated by those skilled in the art that thepharmaceutically acceptable derivatives of the compounds of formula (I)may be derivatised at more than one position.

Preferred pharmaceutically acceptable derivatives of the compounds offormula (I) are pharmaceutically acceptable salts and solvates thereof.

Suitable pharmaceutically acceptable salts of the compounds of generalformula (I) include acid addition salts formed with pharmaceuticallyacceptable organic or inorganic acids for example, hydrochlorides,hydrobromides, sulphates, alkyl- or arylsulphonates (e.g.methanesulphonates or p-toluenesulphonates), phosphates, acetates,citrates, succinates, tartrates, fumarates and maleates. Dihydrochloridesalts are particularly suitable.

Other acids, such as oxalic, while not in themselves pharmaceuticallyacceptable, may be useful in the preparation of salts useful asintermediates in obtaining the compounds of formula (I) and theirpharmaceutically acceptable acid addition salts.

The solvates may, for example, be hydrates.

References hereinafter to a compound according to the invention includesboth compounds of formula (I) and their pharmaceutically acceptablederivatives.

It will be appreciated by those skilled in the art that the compounds offormula (I) contain at least two chiral centres (shown as * in formula(I)) and thus exist in the form of two pairs of optical isomers (i.e.enantiomers) and mixtures thereof including racemic mixtures.

For example the compounds of formula (I) may be either cis isomers, asrepresented by figures (a) and (b), or trans isomers, as represented byfigures (c) and (d), or mixtures thereof.

All of the isomers of the compounds of formula (I) represented by thefigures (a) to (d) and mixtures thereof including racemic mixtures areincluded within the scope of the invention. ##STR5##

The compounds of formula (I) are preferably in the form of their cisisomers (i.e. as represented by figures (a) and (b)). The 2S, 3S isomers(i.e. as represented by figure (b)) are particularly preferred.

Referring to the general formula (I), a C₂₋₄ alkoxy group may be astraight chain or branched chain alkoxy group, for example, ethoxy,propoxy, prop-2-oxy, butoxy, but-2-oxy, 2-methylprop-1-oxy or2-methylprop-2-oxy. A C₁₋₄ alkyl group may be a straight chain orbranched chain alkyl group and may be, for example, methyl, ethyl,propyl, prop-2-yl, butyl, but-2-yl, 2-methylprop-1-yl or2-methylprop-2-yl.

Referring to the general formula (I), a halogen atom may be a fluorine,chlorine, bromine or iodine atom, such as a fluorine, chlorine orbromine atom.

R³ is preferably a hydrogen atom.

R⁴ and R⁵ are preferably hydrogen or halogen, e.g. fluorine, atoms, e.g.R⁴ may represent a halogen, e.g. a fluorine, atom and R⁵ may represent ahydrogen atom. More preferably R⁴ and R⁵ are both hydrogen atoms.

A preferred class of compounds of formula (I) are those wherein R¹ is anethoxy, propoxy, prop-2-oxy, butoxy, but-2-oxy, 2-methylprop-1-oxy or2-methylprop-2-oxy group, R³ is a hydrogen atom and R⁴ and R⁵ arehydrogen or halogen, e.g. fluorine, atoms, more preferably R⁴ and R⁵ areboth hydrogen atoms.

Specific compounds according to the invention include:

(2-(2-Propoxy)-5-(5-trifluoromethyltetrazol-1-yl)benzyl)-(2S,3S!-2-phenylpiperidin-3-yl)amine

(2-(1-Propoxy)-5-(5-trifluoromethyltetrazol-1-yl)benzyl)-(2S,3S!-2-phenylpiperidin-3-yl)amine

(2-(1-Butoxy)-5-(5-trifluoromethyltetrazol-1-yl)benzyl)-(2S,3S!-2-phenylpiperidin-3-yl)amine

(2-(2-Butoxy)-5-(5-trifluoromethyltetrazol-1-yl)benzyl)-(2S,3S!-2-phenylpiperidin-3-yl)amine

(2-(2-Methyl-1-propoxy)-5-(5-trifluoromethyltetrazol-1-yl)benzyl)-( 2S,3S!-2-phenylpiperidin-3-yl)amine

(2-(2-Ethoxy-5-(5-trifluoromethyltetrazol-1-yl)benzyl)-( 2S,3S!-2-4-fluorophenyl)-piperidin-3-yl)amine

and pharmaceutically acceptable derivatives, e.g. salts, especially thedihydrochloride salts, and solvates thereof.

A further specific compound according to the invention includes:

(2-(2-Methyl-2-propoxy)-5-(5-trifluoromethyltetrazol-1-yl)benzyl)-(2S,3S!-2-phenylpiperidin-3-yl)amine

and pharmaceutically acceptable derivatives thereof.

A preferred compound according to the invention is:

(2-Ethoxy-5-(5-trifluoromethyltetrazol-1-yl)benzyl)-(2S,3S!-2-phenylpiperidin-3-yl)amine

and pharmaceutically acceptable derivatives, e.g. salts, especially thedihydrochloride salt, and solvates thereof.

The compounds of the invention are antagonists of tachykinins, includingsubstance P and other neurokinins both in vitro and in vivo and are thusof use in the treatment of conditions mediated by tachykinins, includingsubstance P and other neurokinins.

The compounds of the invention possess NK₁ - receptor binding affinityas determined in vitro by their ability to displace 3H!--substance P(SP) from recombinant human NK₁ receptors expressed in Chinese HamsterOvary (CHO) cell membranes. CHO membranes (3-5 μg protein per tube) wereprepared and incubated with 3H!-SP (0.6-0.8 nM) at 20° C. for 40 min.Non-specific binding was defined as that remaining in the presence of 1μM (+) CP99,994.

The compounds of the invention have been shown to have anti-emeticactivity as indicated by for example their ability to inhibitradiation-induced emesis in the ferret. In this model of emesis theonset of retching and vomiting occurs approximately 20 minutes afterwhole body irradiation (2 Grey═200 Rads). The test compound isadministered (e.g. i.p, p.o., i.v., s.c) immediately after irradiationand its effect on emesis determined by comparison with appropriatecontrols. Anti-emetic activity may also be demonstrated using otheremetogens such as cisplatin and ipecacuanha. Alternatively, the testcompounds may be administered before irradiation or before treatmentwith an emetogen, for example 1.5, 3 or 6 hours before irradiation.

Compounds of the invention have been shown to inhibit radiation-inducedemesis at a dose of 0.1 to 3 mg/kg s.c. in the above test.

The compounds of the invention are potent and specific NK₁ antagonists.Furthermore, they exhibit good oral bioavailability and have anadvantageous duration of action.

Compounds of the invention are useful as analgesics in particular theyare useful in the treatment of traumatic pain such as postoperativepain; traumatic avulsion pain such as brachial plexus; chronic pain suchas arthritic pain such as occurring in osteo-, rheumatoid or psoriaticarthritis; neuropathic pain such as post-herpetic neuralgia, trigeminalneuralgia, segmental or intercostal neuralgia, fibromyalgia, causalgia,peripheral neuropathy, diabetic neuropathy, chemotherapy-inducedneuropathy, AIDS related neuropathy, occipital neuralgia, geniculateneuralgia, glossopharyngeal neuralgia, reflex sympathetic dystrophy,phantom limb pain; various forms of headache such as migraine, acute orchronic tension headache, temporomandibular pain, maxillary sinus pain,cluster headache; odontalgia; cancer pain; pain of visceral origin;gastrointestinal pain; nerve entrapment pain; sport's injury pain;dysmennorrhoea; menstrual pain; meningitis; arachnoiditis;musculoskeletal pain; low back pain e.g. spinal stenosis; prolapseddisc; sciatica; angina; ankylosing spondyolitis; gout; bums; scar pain;itch; and thalamic pain such as post stroke thalamic pain.

Compounds of the invention are also useful as antiinflammatory agents inparticular they are useful in the treatment of inflammation in asthma,influenza, chronic bronchitis and rheumatoid arthritis; in the treatmentof inflammatory diseases of the gastrointestinal tract such as Crohn'sdisease, ulcerative colitis, inflammatory bowel disease, non-steroidalanti-inflammatory drug induced damage and inflammatory and secretoryeffects of bacterial infection, e.g. due to Clostridium difficile;inflammatory diseases of the skin such as herpes and eczema;inflammatory diseases of the bladder such as cystitis and urge (i.e.urinary) incontinence; and eye and dental inflammation, e.g. gingivitisand periodontitis.

Compounds of the invention are also useful in the treatment of allergicdisorders in particular allergic disorders of the skin such asurticaria, and allergic disorders of the airways such as rhinitis.

Compounds of the invention may also be useful in the treatment of CNSdisorders in particular psychoses such as schizophrenia, mania ordementia; cognitive disorders e.g. Alzheimer's disease; anxiety; AIDSrelated dementia; diabetic neuropathy; multiple sclerosis; depression;Parkinson's disease; and dependency on drugs or substances of abuse; andalso the compounds of the invention may act as myorelaxants andantispasmodics.

Compounds of the invention are also useful in the treatment of emesis,i.e. nausea, retching and vomiting. Emesis includes acute emesis,delayed or late emesis and anticipatory emesis. The compounds of theinvention, are useful in the treatment of emesis however induced. Forexample, emesis may be induced by drugs such as cancer chemotherapeuticagents such as alkylating agents, e.g. cyclophosphamide, carmustine,lomustine and chlorambucil; cytotoxic antibiotics, e.g. dactinomycin,doxorubicin, mitomycin-C and bleomycin; anti-metabolites, e.g.cytarabine, methotrexate and 5-fluorouracil; vinca alkaloids, e.g.etoposide, vinblastine and vincristine; and others such as cisplatin,dacarbazine, procarbazine and hydroxyurea; and combinations thereof;radiation sickness; radiation therapy, e.g. irradiation of the thorax orabdomen, such as in the treatment of cancer; carcinoid syndrome;poisons; toxins such as toxins caused by metabolic disorders or byinfection, e.g. gastritis, or released during bacterial or viralgastrointestinal infection; pregnancy; vestibular disorders, such asmotion sickness, vertigo, dizziness and Meniere's disease;post-operative sickness; dialysis-induced emesis; prostaglandin-inducedemesis; gastrointestinal obstruction; reduced gastrointestinal motility;visceral pain, e.g. myocardial infarction or peritonitis; migraine;increased intercranial pressure; decreased intercranial pressure (e.g.altitude sickness); opioid analgesics, such as morphine;gastro-oesophageal reflux disease, acid indigestion, over-indulgence offood or drink, acid stomach, sour stomach, waterbrash/regurgitation,heartburn, such as episodic heartburn, nocturnal heartburn, andmeal-induced heartburn and dyspepsia; organ failure, such as in terminalillness; AIDS and AIDS-related conditions, and treatments thereof; andcyclic vomiting syndrome.

Compounds of the invention are also useful in the treatment ofgastrointestinal disorders such as irritable bowel syndrome; skindisorders such as psoriasis, pruritis and sunburn; vasospastic diseasessuch as angina, vascular headache and Reynaud's disease; cerebralischeamia such as cerebral vasospasm following subarachnoid haemorrhage;fibrosing and collagen diseases such as scleroderma and eosinophilicfascioliasis; disorders related to immune enhancement or suppressionsuch as systemic lupus erythematosus and rheumatic diseases such asfibrositis; disorders caused by a spiral urease-positive gram-negativebacterium such as Helicobacter pylori; and cough.

Compounds of the invention are also useful as cosmetic treatments, forexample in the formulation of cosmetic compositions for sensitive skin.

The invention therefore provides a compound of formula (I) or apharmaceutically acceptable derivative thereof for use in therapy, inparticular in human medicine.

There is also provided as a further aspect of the invention the use of acompound of formula (I) or a pharmaceutically acceptable derivativethereof in the preparation of a medicament for use in the treatment ofconditions mediated by tachykinins, including substance P and otherneurokinins.

In an alternative or further aspect there is provided a method for thetreatment of a mammal, including man, in particular in the treatment ofconditions mediated by tachykinins, including substance P and otherneurokinins, comprising administration of an effective amount of acompound of formula (I) or a pharmaceutically acceptable derivativethereof.

It will be appreciated that reference to treatment is intended toinclude prophylaxis as well as the alleviation of established symptoms.Compounds of formula (I) may be administered as the raw chemical but theactive ingredient is preferably presented as a pharmaceuticalformulation.

Accordingly, the invention also provides a pharmaceutical compositionwhich comprises at least one compound of formula (I) or apharmaceutically acceptable derivative thereof and formulated foradministration by any convenient route. Such compositions are preferablyin a form adapted for use in medicine, in particular human medicine, andcan conveniently be formulated in a conventional manner using one ormore pharmaceutically acceptable carriers or excipients.

Thus compounds of formula (I) may be formulated for oral, buccal,parenteral, topical (including ophthalmic and nasal), transdermal, depotor rectal administration or in a form suitable for administration byinhalation or insufflation (either through the mouth or nose).

For oral administration, the pharmaceutical compositions may take theform of, for example, tablets or capsules prepared by conventional meanswith pharmaceutically acceptable excipients such as binding agents (e.g.pregelatinised maize starch, polyvinylpyrrolidone or hydroxypropylmethylcellulose); fillers (e.g. lactose, microcrystalline cellulose orcalcium hydrogen phosphate); lubricants (e.g. magnesium stearate, talcor silica); disintegrants (e.g. potato starch or sodium starchglycollate); or wetting agents (e.g. sodium lauryl sulphate). Thetablets may be coated by methods well known in the art. Liquidpreparations for oral administration may take the form of, for example,solutions, syrups or suspensions, or they may be presented as a dryproduct for constitution with water or other suitable vehicle beforeuse. Such liquid preparations may be prepared by conventional means withpharmaceutically acceptable additives such as suspending agents (e.g.sorbitol syrup, cellulose derivatives or hydrogenated edible fats);emulsifying agents (e.g. lecithin or acacia); non-aqueous vehicles (e.g.almond oil, oily esters, ethyl alcohol or fractionated vegetable oils);and preservatives (e.g. methyl or propyl-p-hydroxybenzoates or sorbicacid). The preparations may also contain buffer salts, flavouring,colouring and sweetening agents as appropriate.

Preparations for oral administration may be suitably formulated to givecontrolled release of the active compound.

For buccal administration the composition may take the form of tabletsor lozenges formulated in conventional manner.

The compounds of the invention may be formulated for parenteraladministration by bolus injection or continuous infusion. Formulationsfor injection may be presented in unit dosage form e.g. in ampoules orin multi-dose containers, with an added preservative. The compositionsmay take such forms as suspensions, solutions or emulsions in oily oraqueous vehicles, and may contain formulatory agents such as suspending,stabilising and/or dispersing agents. Alternatively, the activeingredient may be in powder form for constitution with a suitablevehicle, e.g. sterile pyrogen-free water, before use.

The compounds of the invention may be formulated for topicaladministration in the form of ointments, creams, gels, lotions,pessaries, aerosols or drops (e.g. eye, ear or nose drops). Ointmentsand creams may, for example, be formulated with an aqueous or oily basewith the addition of suitable thickening and/or gelling agents.Ointments for administration to the eye may be manufactured in a sterilemanner using sterilised components.

Lotions may be formulated with an aqueous or oily base and will ingeneral also contain one or more emulsifying agents, stabilising agents,dispersing agents, suspending agents, thickening agents, or colouringagents. Drops may be formulated with an aqueous or non aqueous base alsocomprising one or more dispersing agents, stabilising agents,solubilising agents or suspending agents. They may also contain apreservative.

For transdermal administration the compounds according to the inventionmay be formulated as creams, gels, ointments or lotions or as atransdermal patch. Such compositions may for example be formulated withan aqueous or oily base with the addition of suitable thickening,gelling, emulsifying, stabilising, dispersing, suspending, and/orcolouring agents.

The compounds of the invention may also be formulated in rectalcompositions such as suppositories or retention enemas, e.g. containingconventional suppository bases such as cocoa butter or other glycerides.

The compounds of the invention may also be formulated as depotpreparations. Such long acting formulations may be administered byimplantation (for example subcutaneously or intramuscularly) or byintramuscular injection. Thus, for example, the compounds of theinvention may be formulated with suitable polymeric or hydrophobicmaterials (for example as an emulsion in an acceptable oil) or ionexchange resins, or as sparingly soluble derivatives, for example, as asparingly soluble salt.

For intranasal administration, the compounds of the invention may beformulated as solutions for administration via a suitable metered orunit dose device or alternatively as a powder mix with a suitablecarrier for administration using a suitable delivery device.

The compositions may contain from 0.1% upwards, e.g. 0.1-99% of theactive material, depending on the method of administration. A proposeddose of the compounds of the invention is 0.05 mg/kg to about 400 mg/kgbodyweight per day e.g. 0.05 mg/kg to 5 mg/kg per day. It will beappreciated that it may be necessary to make routine variations to thedosage, depending on the age and condition of the patient and theprecise dosage will be ultimately at the discretion of the attendantphysician or veterinarian. The dosage will also depend on the route ofadministration and the particular compound selected.

The compounds of formula (I) may, if desired, be administered with oneor more therapeutic agents and formulated for administration by anyconvenient route in a conventional manner. Appropriate doses will bereadily appreciated by those skilled in the art. For example, thecompounds of formula (I) may be administered in combination with asystematic anti-inflammatory corticosteroid such as methyl prednisoloneor dexamethasone, MMP or TNF convertase inhibitors, CD23 or CD4antibodies or a 5HT₃ antagonist such as ondansetron, granisetron ormetoclopramide. The compounds of formula (I) may also be administered incombination with sympathomimetics, such as ephedrine, pseudoephedrineand oxymetazoline, or the compounds may be administered with analgesics,such as non-steroidal antiinflammatory drugs (NSAIDs), opioids e.g.opiate agonists, lipoxygenase inhibitors, cyclooxygenase inhibitors,NMDA antagonists, e.g. glycine antagonists, inhibitors of nitric oxideor its synthesis, sodium channel blockers or local anaesthetics.Compounds which are specific antagonists at NK₁ receptors, such as thecompounds of formula (I), may be administered in combination withcompounds which are specific antagonists at NK₂ receptors.

Compounds of formula (I), and salts and solvates thereof, may beprepared by the general methods outlined hereinafter. In the followingdescription, the groups R¹, R², R³, R⁴ and R⁵ are as previously definedfor compounds of formula (I) unless otherwise stated.

According to a first general process (A), a compound of formula (I) maybe prepared by reacting a compound of formula (II): ##STR6## with acompound of formula (III) ##STR7## to form the intermediate imine, whichmay be isolated if required, followed by reduction of the imine using asuitable metal reducing agent such as a metal hydride, for example aborane hydride, alane hydride or a metal hydride complex like lithiumaluminum hydride or sodium borohydride, or an organo-metallic complexsuch as borane-methyl sulphide, 9-borabicyclononane (9-BBN),triethylsilane, sodium triacetoxyborohydride, sodium cyanoborohydrideand the like. Alternatively, catalytic hydrogenation may be used, forexample using a platinum catalyst in a suitable solvent e.g. ethanol.

The condensation reaction conveniently takes place in a suitable solventsuch as an alcohol (e.g. methanol), an aromatic hydrocarbon (e.g.benzene, toluene or xylene) or a chlorinated hydrocarbon (e.g.dichloromethane or dichloroethane) at a temperature ranging from ambientto the reflux temperature of the reaction mixture. The reactionpreferably takes place in the presence of a catalytic amount of asuitable acidic condensing agent such as p-toluenesulphonic acid oracetic acid and/or a dehydrating agent such as molecular sieves, or thereaction may take place under Dean-Stark conditions.

The reduction step conveniently takes place in a suitable solvent suchas acetonitrile, dimethylformamide, benzene, chlorinated hydrocarbonssuch as dichloromethane or dichloroethane, ethers such as diethyl ether,tetrahydrofuran, dioxane and 1,2-dimethoxyethane and alcohols such asethanol at a temperature ranging from 0° C. to the reflux temperature ofthe reaction mixture.

Process (A) may also take place in one step without isolation of theintermediate imine if the condensation reaction takes place in thepresence of sodium cyanoborohydride or sodium triacetoxyborohydride.Further reduction is therefore unnecessary in this case.

Compounds of formula (II) may be prepared according to conventionalprocedures, for example as described in WO-A-9508549 which isincorporated herein by reference.

Compounds of formula (III) may be prepared by reacting compounds offormula (IV) ##STR8## with an appropriate alkylating agent, such as aC₂₋₄ alkyl bromide or iodide in the presence of a base such as potassiumcarbonate.

Compounds of formula (IV) may be prepared by reacting compounds offormula (V) ##STR9## with hexamethylenetetramine in the presence oftrifluoroacetic acid at elevated temperature.

Compounds of formula (V) may be prepared by reacting the appropriatep-hydroxyaniline, or a protected derivative thereof, with compounds offormula (VI)

    CF.sub.3 --C(OR.sup.7).sub.3                               (VI)

(where R⁷ is methyl or ethyl), for example triethylorthoacetate, inacetic acid followed by reaction with sodium azide at elevatedtemperature and deprotection if necessary.

Compounds of formula (III) may be prepared by oxidising compounds offormula (VII) ##STR10## with a suitable oxidising agent such asmanganese dioxide in a suitable solvent such as an ether, e.g.tetrahydrofuran, at elevated temperature.

Compounds of formula (VII), may be prepared by reducing compounds offormula (VIII) ##STR11## with a suitable reducing agent such as a metalhydride complex such as lithium borohydride in a suitable solvent suchas an ether, e.g. tetrahydrofuran, or an alcohol, e.g. ethanol, or amixture thereof.

Compounds of formula (VIII) may be prepared from the corresponding2-alkoxy-5-amino benzoic acid methyl ester by reacting with compounds offormula (VI) as defined above, e.g. triethyl orthoformate, and sodiumazide in glacial acetic acid and dimethylform-amide at elevatedtemperature.

Suitable 2-alkoxy-5-amino benzoic acid methyl esters are either known ormay be prepared according to methods known for the preparation of knowncompounds e.g. the method described by Bergman et al in Can.J.Chem,(1973), 51, 162-70.

According to a further general process (B), compounds of formula (I) maybe prepared by reduction of compounds of formula (IX) ##STR12## with asuitable reducing agent, such as a metal hydride, for example a boranehydride, in a suitable solvent such as an ether, e.g. tetrahydrofuran,at ambient temperature.

Compounds of formula (IX) may be prepared by reacting compounds offormula (III) with compounds of formula (X) ##STR13## under conditionsas described above for process (A).

Compounds of formula (X) are either known or may be prepared accordingto methods known for the preparation of known compounds, for exampleaccording to the method described in European Patent Application No.EP-A-0436334, incorporated herein by reference.

According to a further general process (C) compounds of formula (I) maybe prepared by reacting a compound of formula (XI) ##STR14## or anamino-protected derivative thereof, with L-C₂₋₄ alkyl where L representsa suitable leaving group such as iodine, bromine, chlorine, OSO₂ R⁶,where R^(c) represents methyl, paratoluoyl or trifluoromethyl, in thepresence of a base, such as potassium carbonate, and a suitable solvent,such as dimethylformamide, at a temperature between 0 and 100° C., e.g.at room temperature, followed by deprotection where necessary.

Compounds of formula (XI) may be prepared by reacting compounds offormula (XII) ##STR15## where R⁸ is C₁₋₄ alkyl, e.g. methyl, withborane-methyl sulphide complex in a suitable solvent, such asdichloromethane, at elevated temperature.

Compounds of formula (XII) may be prepared according to similar methodsdescribed herein for the preparation of compounds of formula (I) andthose methods described in WO-A-9508549.

Suitable protecting groups for the hydroxyl function include benzylgroups which may be introduced and removed according to conventionalprocedures. For example deprotection may be effected by catalytichydrogenation.

Aldehyde functions may be protected as acetals which may be introducedand removed according to conventional procedures. For example,deprotection may be effected by acid hydrolysis.

Amino functions may be protected by, for example, a t-butyl carbamate(BOC) group or a benzyl group which may be introduced and removedaccording to conventional procedures. For example, deprotection of BOCgroups may be effected by acid hydrolysis.

Compounds of formulae (III), (IX) and (XII) are novel and therefore forma further feature of the invention.

Where it is desired to isolate a compound of formula (I) as a salt, forexample a pharmaceutically acceptable salt, this may be achieved byreacting the compound of formula (I) in the form of the free base withan appropriate amount of suitable acid and in a suitable solvent such asan alcohol (e.g. ethanol or methanol), an ester (e.g. ethyl acetate) oran ether (e.g. diethyl ether or tetrahydrofuran).

Pharmaceutically acceptable salts may also be prepared from other salts,including other pharmaceutically acceptable salts, of the compound offormula (I) using conventional methods.

The compounds of formula (I) may readily be isolated in association withsolvent molecules by crystallisation from or evaporation of anappropriate solvent to give the corresponding solvates.

When a specific enantiomer of a compound of general formula (I) isrequired, this may be obtained for example by resolution of acorresponding enantiomeric mixture of a compound of formula (I) usingconventional methods.

Thus, in one example an appropriate optically active acid may be used toform salts with the enantiomeric mixture of a compound of generalformula (I). The resulting mixture of isomeric salts may be separatedfor example by fractional crystallisation, into the diastereoisomericsalts from which the required enantiomer of a compound of generalformula (I) may be isolated by conversion into the required free base.

Alternatively, enantiomers of a compound of general formula (I) may besynthesised from the appropriate optically active intermediates usingany of the general processes described herein.

A particularly suitable route for the preparation of optically activeintermediates of formula (II) from the enantiomeric mixture thereof isby fractional crystallisation using (2R,3R)-bis-(4-methyl-benzoyloxy)-succinic acid. Thus, the cis (S,S) form ofintermediate (II) may be obtained from an enantiomeric mixture thereof(e.g. the racemic mixture) by fractional crystallisation with (2R,3R)-bis-4-methyl-benzoyloxy)-succinic acid in a suitable solvent, suchas an aqueous alcohol, e.g. aqueous ethanol, isolating the resultingsalt and converting it into the corresponding optically active free baseby conventional procedures for example using aqueous ammonia.

Alternative methods for preparing and resolving2-phenyl-3-aminopiperidine are described in WO-A-9427966, incorporatedherein by reference.

Specific enantiomers of a compound of formula (I) may also be obtainedby chromatography of the corresponding enantiomeric mixture on a chiralcolumn, for example by chiral preparative h.p.I.c.

Specific diastereoisomers of a compound of general formula (I) may beobtained by conventional methods for example, by synthesis from anappropriate asymmetric starting material using any of the processesdescribed herein, or by conversion of a mixture of isomers of a compoundof general formula (I) into appropriate diastereoisomeric derivativese.g. salts which can then be separated by conventional means e.g. bychromatography or by fractional crystallisation. Alternatively, thediastereosiomers may be separable without the need for furtherderivatization.

Standard resolving methods are described for example in `Stereochemistryof Carbon Compounds` by E. L. Eliel (McGraw Hill, 1962) and `Tables ofResolving Agents` by S. H. Wilen.

The various general methods described above may be useful for theintroduction of the desired groups at any stage in the stepwiseformation of the required compound, and it will be appreciated thatthese general methods can be combined in different ways in suchmulti-stage processes. The sequence of the reactions in multi-stageprocesses should of course be chosen so that the reaction conditionsused do not affect groups in the molecule which are desired in the finalproduct.

The invention is further illustrated by the following Intermediates andExamples which are not intended as a limitation of the invention. Alltemperatures are in 0° C. Flash column chromatography (FCC) was carriedout on silica (Merck 9385). The following abbreviations are used:ether-diethyl ether.

INTERMEDIATE 1 N-(4-Benzyloxy-phenyl)-2,2,2-trifluoro-acetamide

A mixture of 4-benzyloxyaniline hydrochloride (0.19 mol) indichloromethane (750 ml) at 0° under nitrogen was treated dropwise withtrifluoroacetic anhydride (27.6 ml) then triethylamine (60 ml). After 24h the mixture was poured into t-butyl methyl ether (1.5 l) and waswashed with 2N hydrochloric acid (1 l). The organic phase was dried(MgSO₄) and evaporated in vacuo to give the title compound as a whitesolid (52.3 g).

T.I.c. (cyclohexane/ethylacetate (9:1)) Rf 0.36.

INTERMEDIATE 2(4-Benzyloxy-phenyl)-(1-chloro-2,2,2-trifluoro-ethylidene)-amine

A mixture of resin-supported triphenylphosphine (3 mmoltriphenylphosphine/g resin; 58.6 g) andN-4-benzyloxy-phenyl)-2,2,2-trifluoro-acetamide (20.8 g) in carbontetrachloride (800 ml) was heated to reflux under nitrogen for 18 h. Themixture was allowed to cool then filtered, washing the resin withdichloromethane (1 l ) and ether (1 l). The organics were concentratedin vacuo to give the title compound as a yellow solid (20.7 g).

T.I.c. (Cyclohexane/ethyl acetate (9:1)) Rf 0.81

INTERMEDIATE 3 1-(4-Benzyloxy-phenyl)-5-trifluoromethyl-1H-tetrazole

(4-Benzyloxy-phenyl)-(1-chloro-2,2,2-trifluoro-ethylidene)-amine (66mmol) was added to a stirred flask of glacial acetic acid (250 ml) at70° under nitrogen. After 4 min sodium azide (210 mmol) was added andheating was continued for 3 h. After cooling the mixture was filtered,the filtrate poured into water (750 ml) then extracted withdichloromethane (500 ml×3). The combined organic extracts were dried(Na₂ SO₄) and evaporated in vacuo. Purification by FCC usinghexane-ethyl acetate (19:1) gave the title compound as a white solid(14.5 g).

T.I.c. (Cyclohexane/ethyl acetate (19:1) Rf 0.22

INTERMEDIATE 4 4-(5-Trifluoromethyl-tetrazol-1-yl)-phenol

A solution of 1-(4-benzyloxy-phenyl)-5-trifluoromethyl-1H-tetrazole(45.3 mmol) in ethanol (100 ml) and tetrahydrofuran (100 ml) washydrogenated at room temperature and atmospheric pressure over 10%palladium-carbon catalyst (6 g). After 2 h, the mixture was filtered andthe filtrate was evaporated to give the title compound (10.4 g) as acream solid.

T.I.c. (Dichlormethane/ethanol/ammonia(200:8:1)) Rf 0.3.

INTERMEDIATE 52-Hydroxy-5-(5-trifluoromethyl-tetrazol-1-yl)-benzaldehyde

A solution of 4-(5-trifluoromethyl-tetrazol-1-yl)-phenol (45 mmol) intrifluoroacetic acid (200 ml) and hexamethylenetetramine (186.9 mmol)was heated at 100°, under nitrogen for 16 h. The reaction mixture wasquenched with 2N sulphuric acid (250 ml) and extracted with ether (3×250ml)). The combined organics were dried (Na₂ SO₄) and evaporated to givea dark yellow oil. Purification by FCC (hexane/ether (2:1)) afforded thetitle compound (8.8 g) as a pale yellow solid. T.I.c. (hexane/ether(2:1)) Rf 0.36

INTERMEDIATE 62-Methoxy-5-(5-trifluoromethyl-tetrazol-1-yl)-benzaldehyde

A mixture of 2-hydroxy-5-(5-trifluoromethyl-tetrazol-1-yl)benzaldehyde(1.56 mmol), potassium carbonate (7.8 mmol) and methyl iodide (7.8mmol), in acetone (25 ml) was stirred for 18 h at 23° under nitrogen.Water (150 ml) was added and the mixture extracted with diethyl ether(3×50 ml). The combined organic extracts were washed with saturatedbrine, dried (Na₂ SO₄) and evaporated to give the title compound as ayellow solid (0.48 g).

T.I.c. (ether/hexane (2:1)) Rf 0.38.

INTERMEDIATE 7 2Methoxy-5-(5-trifluoromethyl-tetrazol-1-yl)-benzyl!-(2S,3S!-2-phenyl-piperidin-3-yl)-amine dihydrochloride

A mixture of 2S!-phenyl-piperidin-( 3S!-ylamine (1.14 mmol),2-methoxy-5-(5-trifluoromethyl-tetrazol-1-yl)-benzaldehyde (1.2 mmol);sodium triacetoxyborohydride (2.37 mmol) and acetic acid (3 drops) indichloromethane (25 ml) was stirred at 23° under nitrogen for 64 h. 2Nsodium carbonate solution (50 ml) was added and the mixture extractedwith dichloromethane (3×25 ml). The combined extracts were washed withsaturated brine (50 ml), dried (MgSO₄) and evaporated. Purification byFCC with dichloromethane/ethanol/ammonia (400:10:1→100:10:1) gave acolourless viscous oil. This was dissolved in methanol (10 ml) andtreated with 2N ethereal hydrogen chloride (˜10 ml). Evaporation invacuo and trituration with i-propyl acetate gave the title compound as awhite solid (210 mg). T.I.c. (Dichloromethane/ethanol/ammonia(200:10:1)) Rf 0.39. Optical Rotation (c 3 mg/ml. water) +50.35°.

INTERMEDIATE 8 2-Hydroxy-5-(5-trifluoromethyl-tetrazol-1-yl)-benzyl!-(2S,3S!-2-phenylpiperidin-3-yl)amine

A suspension of 2-methoxy-5-(5-trifluoromethyl-tetrazol-1-yl)benzyl!-(2S,3S!-2-phenylpiperidin-3yl)amine dihydrochloride (1.01 g, 2 mmol) inchloroform (20 ml) was stirred at room temperature and treated withtriethylamine, (0.58 ml, 406 mg, 4 mmol) to give a clear solution. Thiswas then treated slowly with a solution of boron tribromide:dimethylsulfide complex (20 ml of 1M solution in dichloromethane; 20mmol) and the reaction mixture was refluxed under nitrogen for 3 days .Further reagent (10 ml, 10 mmol) was then added and after a further 3days the mixture was cooled in an ice-bath, stirred and treated withmethanol (40 ml). The mixture was evaporated to dryness. This treatmentwas repeated twice further. The resulting oil was partitioned betweenethyl acetate (100 ml) and saturated aqueous sodium bicarbonate (100ml). The aqueous phase was extracted with further ethyl acetate (50 ml)after pH adjustment (to pH ca 8). Combined extracts were washed withbrine (100 ml) dried (MgSO₄) and evaporated to a brown foam, which waschromatographed on silica (Merck 9385) eluting with 2% then 5% methanolin dichloromethane. The required fractions were combined and evaporatedto give the title compound as a light brown foam (672 mg), mass spectrum(thermospray +ve) m/e 419 (MH⁺).

INTERMEDIATE 9 3-{tert-Butoxycarbonyl-2-hydroxy-5-(5-trifluoromethyl-tetrazol-1-yl)-bensyl!-amino}-2S,3S!-2-phenylpiperidine-1carboxylic acid tert-butyl ester

A solution of 2-hydroxy-5-(5-trifluoromethyl-tetrazol-1-yl)-benzyl!-(2S,3S!-2-phenylpiperidine-3-yl)amine (418 mg, mmol) in dichloromethane(5 ml) was treated with di-t-butyldicarbonate (240 mg, 1.1 mmol) and thesolution was stirred for 19 h at room temperature. Further reagent wasthen added (240 mg) and after a further day the solution was evaporatedto dryness. The resulting gum was chromatographed on silica (Merck 9385;70 g) eluting with 3:1 then 1:1 cyclohexane:ethyl acetate. The requiredfractions were combined and evaporated to provide the title compound asa light brown foam (487 mg), υ(CHBr₃) 1663 and 1690 cm⁻¹ (carbamateC═O).

INTERMEDIATE 10 3{-tert-Butoxycarbonyl-2-ethoxy-5-(5-trifluoromethyl-tetrazol-1-yl)-benzyl!-amino}-2S,3S!-2-phenylpiperidine-1-carboxylic acid tert-butyl ester

A solution of 3-{tert-butoxycarbonyl2-hydroxy-5-(5-trifluoromethyl-tetrazol-1-yl)-benzyl!-amino}-(2S,3S!-2-phenylpiperidine-1-carboxylic acid tert-butyl ester (300 mg,0.48 mmol) in dimethylformamide (1 ml) containing a suspension of finelyground potassium carbonate (83 mg, 0.6 mmol) was stirred at roomtemperature and treated with ethyl iodide (47 mg, 0.3 mmol). After 2 hfurther reagent was added (47 mg) and after 4 h the reaction mixture wasevaporated to dryness. The residue was partitioned between ethyl acetate(50 ml) and saturated aqueous sodium bicarbonate (50 ml). The organicphase was washed with brine (2×50 ml), dried (MgSO₄) and evaporated to ayellow gum. This was chromatographed on silica (Merck 9385; 30 g)eluting with 3:1 cyclohexane:ethyl acetate. The required fractions werecombined and evaporated to provide the title compound as a white foam(222 mg), mass spectrum (thermospray +ve) m/e 647 (MH⁺).

Similarly prepared:--

INTERMEDIATE 11 3-{tert-Butoxycarbonyl-2-(1-propoxy)-5-(5-trifluoromethyl-tetrazol-1-yl)-benzyl!-amino}-2S,3S!-2-phenylpiperidine-1-carboxylic acid tert-butyl ester

From 3-{tert-butoxycarbonyl-2-hydroxy-5-(5-trifluoromethyl-tetrazol-1-yl)-benzyl!-amino}-2S,3S!-2-phenylpiperidine-1-carboxylic acid tert-butyl ester (400 mg)and 1-iodopropane (111 mg, 0.66 mmol) to give the title compound as awhite foam (167 mg), mass spectrum (thermospray +ve) m/e 661 (MH⁺).

INTERMEDIATE 12 3-{tert-Butoxycarbonyl-2-(1-butoxy)-5-(5-trifluoromethyl-tetrazol-1-yl)-benzyl!-amino}(2S,3S!-2-phenylpiperidine-1-carboxylic acid tert-butyl ester

From 3-{tert-butoxycarbonyl-2-hydroxy-5-(5-trifluoromethyl-tetrazol-1-yl)-benzyl!-amino}-2S,3S!-2-phenylpiperidine-1-carboxylic acid tert-butyl ester (402 mg,0.65 mmol) and 1-bromobutane (212 mg, 1.56 mmol) to give the titlecompound as a white foam (352 mg), mass spectrum (thermospray +ve) m/e675 (MH⁺).

INTERMEDIATE 13 3-{tert-Butoxycarbonyl-2-(2-methyl-1-propoxy-5-(5-trifluoromethyl-tetrazol-1-yl)-benzyl!-amino}-2S,3S!-2-phenylpiperidine-1-carboxylic acid tert-butyl ester.

From3-{tert-butoxycarbonyl-2-hydroxy-5-(5-trifluoromethyl-tetrazol-1-yl)-benzyl!-amino}-2S,3S!-2-phenylpiperidine-1-carboxylic acid tertbutyl ester (400 mg,0.65 mmol) and 1-iodo-2-methylpropane (710 mg, 3.9 mmol) at 40-50° C. togive the title compound as a pale yellow foam (190 mg), mass spectrum(thermospray +ve) m/e 675 (MH⁺).

INTERMEDIATE 142-(2-Butoxy)-5-(5-trifluoromethyl-tetrazol-1-yl)!-benzaldehyde

A solution of 2-hydroxy-5-(5-trifluoromethyl-tetrazol-1-yl)-benzaldehyde(250 mg, 0.97 mmol) in dimethylformamide (10 ml) was stirred at roomtemperature and treated with potassium carbonate (134 mg, 0.97 mmol) and2-iodobutane (267 mg. 1.45 mmol). After ca 18 h further 2-iodobutane wasadded (267 mg, 1.45 mmol) and the mixture was heated at 50° C. for 3days. It was then partitioned between ethyl acetate (50 ml) and2M-hydrochloric acid (25 ml). The organic phase was washed with2M-hydrochloric acid (2×25 ml) and saturated brine (3×25 ml), dried(MgSO₄) and evaporated to a yellow oil. This was purified bychromatography on silica (Merck 9385; 20 g) eluting with 3:1cyclohexane:ethyl acetate. The required fractions were combined andevaporated to give the title compound as a white foam (240 mg), υ(KBrpowder) 1688 cm⁻¹ (C═O aldehyde).

INTERMEDIATE 15 2S!-(4-Fluoro-phenyl)-piperidin- 3S!-yl-amine2R,3R!-bis(4-methyl-benzoyloxy)-succinate

(2R,3R)-bis-(4-methyl-benzoyloxy)-succinic acid (2.0 g) was addedportionwise over 5 min. to a stirred solution of racemic2-(4-fluoro-phenyl)-piperidin-3-ylamine (1.0 g) in ethanol and water at60°. The solution was then allowed to stir for 0.5 h at a temperaturebetween 60-70°. The solution was allowed to cool overnight at ambienttemperature. The solid material was collected and dried in vacuo at 70°(803.5 mg). δ(CD₃ OD) includes 1.5-2.2 (m, 5H), 2.4 (s, 6H), 2.85-3.05(m, 1H), 3.5-3.6 (m, 1H), 4.27 (d, 1H, J=2 Hz), 5.86 (s, 2H), 7.0 (t,2H, J=8.7 Hz), 7.3 (d, 4H, J=8.5 Hz), 7.45 (dd, 2H, J=8.7 and 5 Hz).Chiral HPLC on a CHIRALCEL-OD-H column eluting with hexane containing 2%isopropyl alcohol showed only one enantiomer (t_(R) =35.83 mins). T.I.c.(cyclohexane/ethylacetate (9:1)) Rf 0.36

EXAMPLE 1 2-Ethoxy-5(5-trifluoromethyl-tetrazol-1-yl)-benzyl!-(2S,3S!-2-phenylpiperidine-3-yl)amine dihydrochloride

A solution of 3-{tert-butoxycarbonyl-2-ethoxy-5-(5-trifluoromethyl-tetrazol-1-yl)-benzyl!-amino}-(2S,3S!-2-phenylpiperidine-1-carboxylic acid tertbutyl ester (291 mg,0.45 mmol) in 4M-hydrogen chloride in dioxan (3 ml) was kept at roomtemperature for 3.25 h and then evaporated. The residue was trituratedwith ethanol to give the title compound as a white solid which was driedat 40° C. under vacuum (110 mg). Found C, 50.66; H. 5.23; N, 15.94; C₂₂H₂₅ F₃ N₆ O.2HCl (519.4) requires C, 50.87; H, 5.24; N, 16.18%. Massspectrum (thermospray +ve) m/e 447 (MH⁺).

Similarly prepared:--

EXAMPLE 2 2-(1-Propoxy)-5-(5-trifluoromethyl-tetrazol-1-yl)-benzyl!-(2S,3S!-2-phenylpiperidin-3-yl)amine dihydrochloride

From 3{tert-Butoxycarbonyl-2-(1-propoxy)-5-(5-trifluoromethyl-tetrazol-1-yl)-benzyl!-amino}-2S,3S!-2-phenylpiperidine-1-carboxylic acid tert-butyl ester (268 mg,0.4 mmol) using 4M-hydrogen chloride in dioxan (2 ml) to give the titlecompound as a white solid (93 mg). Found C, 51.04; H, 5.52; N, 15.24;C₂₃ H₂₇ F₃ N₆ O.2HCl.0.4H₂ O (540.64) requires C, 51.10; H, 5.56; N,15.54%. Mass spectrum (thermospray +ve) m/e 461 (MH⁺).

EXAMPLE 3 2-(1-Butoxy)-5-(5-trifluoromethyl-tetrazol-1-yl)-benzyl!-(2S,3S!-2-phenylpiperidin-3-yl)amine dihydrochloride

From 3-{tert-butoxycarbonyl-2-(1-butoxy)-5-(5-trifluoromethyl-tetrazol-1-yl)-benzyl!-amino}-2S,3S!-2-phenylpiperidine-1-carboxylic acid tert-butyl ester (345 mg,0.51 mmol) using 4M-hydrogen chloride in dioxan (5 ml) at 40° C. to givethe title compound as a white crystals from ethanol (218 mg). Found C,51.78; H, 5.62; N, 15.13; C₂₄ H₂₉ F₃ N₆ O.2HCl.0.5H₂ O (556.46),requires C,51.80; H, 5.80; N, 15.10%. Mass spectrum (thermospray +ve)m/e 475 (MH⁺).

EXAMPLE 42-(2-Methyl-1-propoxy)-5-(5-trifluoromethyl-tetrazol-1-yl)-benzyl!-(2S,3S!-2-phenylpiperidin-3-yl)amine dihydrochloride

From 3-{tert-Butoxycarbonyl-2-(2-methyl-1-propoxy)-5-(5-trifluoromethyl-tetrazol-1-yl)benzyl!-amino}-2S,3S!-2-phenylpiperidine-1-carboxylic acid tert-butyl ester (184 mg,0.27 mmol) and 4M-hydrogen chloride in dioxan (10 ml) at 44° C. to givethe title compound as a white solid (156 mg), mass spectrum (thermospray+ve) m/e 475 (MH⁺). R_(F) 0.5 (100:8:1 dichloromethane:ethanol:ammonia).

EXAMPLE 5 2-(2-Propoxy)-5-(5-trifluoromethyl-tetrazol-1-yl)-benzyl!-(2S,3S!-2-phenylpiperidin-3-yl)amine dihydrochloride

A solution of 2-hydroxy-5-(5-trifluoromethyl-tetrazol-1-yl)benzyl!-(2S,3S!-2-phenylpiperidine-3-yl)amine (672 mg, 1.6 mmol) indimethylformamide (5 ml) containing a suspension of potassium carbonate,(225 mg, 1.6 mmol) was stirred at room temperature for 10 minutes andthen treated with 2-iodopropane (80 μl, 136 mg, 0.8 mol). Furtheralkylating agent was added after 18 h (80 μl) and after 3 days (80 μl).After an additional day the reaction mixture was evaporated to dryness.The residue was partitioned between ethyl acetate (100 ml) and saturatedaqueous sodium bicarbonate (100 ml). The organic phase was washed withfurther bicarbonate (100 ml) and brine (2×100 ml), dried (MgSO₄) andevaporated to a brown oil which was chromatographed on silica (Merck7734; 150 g) eluting with 5% then finally 10% methanol indichloromethane. The required fractions were combined and evaporated toprovide a yellow foam (292 mg). This (282 mg) was dissolved in hotethanol (6 ml) and the solution was treated with concentratedhydrochloric acid (120 μl). The crystals were filtered off, washed withethanol and dried to give the title compound as a white crystallinesolid (294 mg). δ(D₂ O) 1.22 (3H, d, J=6 Hz), 1.27 (3H, d, J=6 Hz),2.0-2.36 (3H, m), 2.46 (1H, m), 3.31 (1H, m), 3.6-3.78 (1H, m), 3.86(1H, d, 4 Hz), 4.18 (2H, Abq, J=14 Hz), 4.59 (1H, sept, J=6 Hz), 4.89(1H, d, 3 Hz), 7.14 (1H, d, J=9 Hz), 7.21 (1H, d, J=9 Hz), 7.38-7.56(5H, m), 7.65 (1H, dd, J=3, 9 Hz). Found: C, 51.47; H, 5.52, N, 15.52,F, 10.7; C₂₃ H₂₇ F₃ N₆ O (460.5) 2HCl (533.43) requires C, 51.79, H,5.48; N, 15.75; F, 10.68%.

EXAMPLE 6 2-(2-Butoxy)-5-(5-trifluoromethyl-tetrazol-1-yl)-benzyl!-(2S,3S!-2-phenylpiperidin-3-yl)amine dihydrochloride

A solution of2-(2-butoxy-5-(5-trifluoromethyl-tetrazol-1-yl)!-benzaldehyde (100 mg,0.32 mmol) and ( 2S,3S!-2-phenylpiperidin-3-yl)amine (56 mg, 0.32 mmol)in glacial acetic acid (4 ml) and dichloromethane (4 ml) was stirred atroom temperature and treated with sodium triacetoxyborohydride (108 mg,0.51 mmol) in acetic acid (2 ml). After 24 h the solvent was evaporatedand the residue was partitioned between ethyl acetate (25 ml) and2M-sodium carbonate (25 ml). The aqueous phase was extracted withfurther ethyl acetate (2×25 ml). Combined organic phases were dried (Na₂SO₄) and evaporated to an oil. This was dissolved in hot ethanol (1 ml)and the solution was treated with concentrated hydrochloric acid (0.7mmol) to give the title compound as a cream solid (140 mg), massspectrum (thermospray +ve) m/e 475 (MH⁺). R_(F) 0.37 (100:8:1dichloromethane:ethanol:ammonia).

EXAMPLE 7 (2-(2-Ethoxy-5(5-trifluoromethyltetrazol-1-yl)benzyl)-(2S,3S!-2-(4-fluorophenyl)-piperidin-3-yl)amine dihydrochloride

A suspension of 2S!-(4-Fluoro-phenyl)-piperidin- 3S!-yl-amine2R,3R!-bis(4-methyl-benzoyloxy)-succinate (157 mg, 0.27 mmol) indichloromethane (anhydrous; 3 ml) was stirred at room temperature andtreated with triethylamine (78 μl, 55 mg, 0.54 mmol) to give a solution.This was treated with2-(2-ethoxy-5-(5-trifluoromethyl-tetrazol-1-yl)!-benzaldehyde (77 mg,0.27 mmol), acetic acid (glacial; 15 μl, 16 mg, 0.26 mmol) and sodiumtriacetoxyborohydride (86 mg, 0.40 mmol). After 2.5 h the solution wasevaporated to dryness. The residue was partitioned between ethyl acetate(50 ml) and saturated aqueous sodium bicarbonate (50 ml). The organicphase was washed with water (50 ml) and brine (2×50 ml), dried (MgSO₄)and evaporated to a yellow oil, (118 mg, 94%). Mass spectrum showed MH⁺465.

The entire sample was dissolved in boiling ethanol (ca 3 ml) and thesolution was treated with concentrated hydrochloric acid (42 μl, 0.5mmol). The white crystals were filtered off and dried at 40° C. undervacuum, (68 mg, 47%).

Microanalysis

Found: C, 49.02; H, 4.82; N, 15.47; C₂₂ H₂₄ F₄ N₆ 0.2HCl requires C,49.17; H, 4.88; N, 15.64%.

PHARMACY EXAMPLES Example A Sterile Formulation

    ______________________________________                     mg/ml    ______________________________________    Compound of the invention                            0.3   mg    Sodium Chloride USP     6.0   mg    Sodium Acetate USP      2.6   mg    Acetic Acid             1.1   mg    Water for Injection USP qs to                            1     ml    ______________________________________

The components are dissolved in a portion of the water for injection andthe solution made up to final volume to provide 0.25 mg/ml of thecompound of the invention.

The solution may be packaged for injection, for example by filling andsealing in ampoules, vials or syringes. The ampoules, vials or syringesmay be aseptically filled and/or terminally sterilised by, for example,autoclaving at 121° C.

Tablets for Oral Administration

Tablets may be prepared by the normal methods such as direct compressionor wet granulation.

The tablets may be film coated with suitable film forming materials,such as Opadry White, type YS-1-7027, using standard techniques.Alternatively the tablets may be sugar coated.

Example B

    ______________________________________    Direct Compression Tablet                      mg/Tablet    ______________________________________    Compound of the invention                           0.6     mg    Magnesium Stearate     0.75    mg    Avicel PH102 qs        150.00  mg    ______________________________________

The compound of the invention is passed through a 30 mesh sieve andblended with Avicel PH102 and magnesium stearate. The resultant mix iscompressed into tablets using a suitable tablet machine fitted with9/32" diameter punches.

Example C Wet Granulation

A formulation as described in Example B may be used. The compound of theinvention (dihydrochloride) is dissolved in a suitable volume ofgranulating solution (purified water or 10% PVP K29/32 in water). Afterdrying, the granules are screened, for example through 20 mesh screen,and blended with magnesium stearate. The granules are then compressedinto tablets as described in Example B.

Example D Suppository

    ______________________________________    Compound of the invention                           10.0    mg    Witepsol W32, hard fat qs                           2000.0  mg    ______________________________________

Blend micronized drug in a portion of the melted Witepsol W32 atapproximately 36° C. for approximately 15 minutes in a high speed mixer.Incorporate the homogenized slurry into the remaining portion of themelted Witepsol W32 and blend at approximately 36° C. until satisfactorydispersion is achieved. Fill moulds with 2000 mg formulation.

Example E Capsule

    ______________________________________                    mg/capsule    ______________________________________    Compound of the invention                           12.0   mg    Polyethylene glycol    92.89  mg    Propylene glycol qs    200    mg    ______________________________________

Blend together polyethylene glycol and propylene glycol using heat asnecessary. Stir until homogeneous. Add micronised compound of theinvention to blend. Mix until homogenous. Fill into an appropriategelatin mass to give soft gelatin capsules containing 200 mg of theformulation.

Example F Oral Syrup

    ______________________________________                    mg/ml    ______________________________________    Compound of the invention                           6.0    mg    Sucrose                200    mg    Methylparaben          1.2    mg    Propylparaben          0.15   mg    Flavouring             1.5    mg    Citric Acid            0.1    mg    Purified Water qs      1      ml    ______________________________________

Dissolve the parabens in a small portion of the water that has beenheated to approximately 90° C. Add the paraben solution to a largeportion of the remaining water with mixing. Add and dissolve the othercomponents. Bring the formulation to final volume and mix untilhomogenous. Fill the formulation into a container, such as a unit dosecup or a bottle for multiple-dose use.

Biological Data

As mentioned hereinbefore, compounds of the invention have been shown toinhibit radiation-induced emesis in the ferret using the test asdescribed hereinbefore. More specifically the compound of Example 1,2-Ethoxy-5-(5-trifluoromethyl-tetrazol-1-yl)-benzyl!-(2S,3S!-2-phenylpiperidine-3-yl)amine dihydrochloride, inhibitedradiation-induced emesis in the ferret, administering the compound 1.5hours prior to irradiation, at a dose of 0.1 mg/kg s.c.

No apparent adverse or toxic effects were observed during the above invivo tests due to the administration of the compounds of the invention.

We claim:
 1. . A compound of formula (I) ##STR16## wherein R¹ is a C₂₋₄alkoxy group; R² is ##STR17## R³ is a hydrogen or halogen atom; R⁴ andR⁵ may each independently represent a hydrogen or halogen atom, or aC₁₋₄ alkyl, C₁₋₄ alkoxy or trifluoromethyl group;or a pharmaceuticallyacceptable salt or solvate thereof.
 2. A compound according to claim 1wherein R³, R⁴ and R⁵ are hydrogen atoms.
 3. A compound according toclaim 1 wherein R¹ is an ethoxy, propoxy, prop-2-oxy, butoxy, but-2-oxy,2-methylprop-1-oxy or 2-methylprop-2-oxy group.
 4. A compound selectedfrom(2-(2-Propoxy)-5-(5-trifluoromethyltetrazol-1-yl)benzyl)-(2S,3S!-2-phenylpiperidin-3-yl)amine(2-(1-Propoxy)-5-(5-trifluoromethyltetrazol-1-yl)benzyl)-(2S,3S!-2-phenylpiperidin-3-yl)amine(2-(1-Butoxy)-5-(5-trifluoromethyltetrazol-1-yl)benzyl)-(2S,3S!-2-phenylpiperidin-3-yl)amine(2-(2-Butoxy)-5-(5-trifluoromethyltetrazol-1-yl)benzyl)-(2S,3S!-2-phenylpiperidin-3-yl)amine(2-(2-Methyl-1-propoxy)-5-(5-trifluoromethyltetrazol-1-yl)benzyl)-(2S,3S!-2-phenylpiperidin-3-yl)amine(2-(2-Ethoxy-5-(5-trifluoromethyltetrazol-1-yl)benzyl)-(2S,3S!-2-(4-fluorophenyl)-piperidin-3-yl)amine or a pharmaceuticallyacceptable salt or solvate thereof. 5.(2-Ethoxy-5-(5-trifluoromethyltetrazol-1-yl)benzyl)-(2S,3S!-2-phenylpiperidin-3-yl)amineor a pharmaceutically acceptable salt or solvate thereof.
 6. A compoundaccording to claim 4 in the form of its dihydrochloride salt.
 7. Acompound according to claim 1 for use in therapy.
 8. A pharmaceuticalcomposition comprising a compound according to claim 1 or apharmaceutically acceptable salt or solvate thereof, together with apharmaceutically acceptable carrier.
 9. A method for the treatment ofconditions mediated by tachykinins, including substance P and otherneurokinins, in a mammal wherein the conditions are susceptible totreatment by antagonism of tachykinins comprising administration of aneffective amount of a compound according to claim 1 or apharmaceutically acceptable salt or solvate thereof.
 10. A process forpreparing a compound of formula (I) as defined in claim 1, or apharmaceutically acceptable derivative thereof which comprises:(A)reacting a compound of formula (II) ##STR18## with a compound of formula(III) ##STR19## followed by reduction: or (B) reduction of a compound offormula (IX) ##STR20## with a suitable reducing agent: or (C) reacting acompound of formula (XI) ##STR21## or an amino-protected derivativethereof, with L-C₂₋₄ alkyl where L represents a suitable leaving group,in the presence of a base, followed by deprotection where necessary.